Placental-vascular system communication during obese diabetic pregnancy

• Grant number: 25/22337-4
• Support Opportunities: Scholarships abroad - Research
• Start date: March 01, 2026
• End date: August 31, 2026
• Field of knowledge: Health Sciences - Nutrition - Nutrition Biochemistry
• Principal Investigator: Lila Missae Oyama
• Grantee: Lila Missae Oyama
• Host Investigator: Susan Ozanne
• Host Institution: Escola Paulista de Medicina (EPM). Universidade Federal de São Paulo (UNIFESP). Campus São Paulo. São Paulo , SP, Brazil
• Institution abroad: University of Cambridge, England

Abstract

Studies show that a metabolic disorder during pregnancy can influence fetal growth and increase the risk of both mother and offspring developing metabolic diseases in adulthood. Evidence from the literature demonstrated that both maternal malnutrition and overnutrition during pregnancy can program events that include permanent changes in the function of many tissues (e.g. adipose tissue, heart, liver, muscle). However, the molecular mechanisms involved in mediating the effects of suboptimal nutrition during pregnancy and long-term maternal and offspring health have not yet been fully revealed.Maternal obesity increases the risk of pregnancy complications, including gestational diabetes and preeclampsia, which are linked to an increased long-term cardiovascular and metabolic disease risk for both the mother and offspring. Women with obesity have an elevated risk for adverse cardiovascular outcomes during pregnancy and exhibit poorer long-term cardiovascular health compared to lean pregnancy and even to nulliparous women with obesity. The biological mechanisms underlying this long-term impact on maternal cardiovascular health are not yet understood.During gestation, the normal development of the fetus depends on a healthy intrauterine environment, and the placenta plays a fundamental role in controlling communication between the mother and the growing baby. Placental extracellular vesicles (PEVs) play a crucial role in regulating pregnancy, coordinating both local and systemic processes. They function as key mediators of maternofetal communication, exerting influence on a variety of maternal and fetal tissues and organs.Dysregulated placental communication, particularly via extracellular vesicles (EVs), may harm long-term maternal cardiovascular health. In preeclampsia, a placental hypertensive disorder, the dysfunctional placenta releases factors (e.g., sFlt-1, inflammatory cytokines) that cause endothelial injury, vasoconstriction, and hypertension. We have recently shown that mouse placenta EVs are taken up by human umbilical vein endothelial cells (HUVECs), and cardiomyocyte cell lines in-vitro, implying EVs as a mode of communication between the placenta and recipient cardiovascular cells.In the context of metabolic programming, questions raised by the group of Professor Ozanne are (1) how do EVs released by the placenta, during pregnancy, transmit information to the maternal body impacting on its adaptation to pregnancy and to the fetus, controlling its development and (2) what changes in the content of EVs can occur in diseases such as gestational diabetes and what are the metabolic repercussions of these on immediate and long-term maternal and offspring health. To address these questions, the group collected placentas from mice treated with an obesogenic diet, maintained them in culture medium and isolated EVs that were secreted. These isolated EVs were then incubated with different cell lines in order to highlight which tissues placental EVs had the potential to fuse with. Preliminary results showed that there was tissue specificity in the capacity of the placental EVs to fuse.In this project, we will therefore establish the functional consequences of the uptake of placental EVs from lean and obese mouse pregnancies (e.g. effects on oxidative stress and production of reactive oxygen species on endothelial cell functions in vitro. This will include effects on proliferation, Nitric oxide signalling, oxidative stress, angiogenesis/tubulogenesis, migration, apoptosis and permeability in human (HUVECs, HUAECs, HAOECs and human pulmonary artery endothelial cells) and mouse endothelial cells (C166 or mouse lung ECs from immorto mice).